Pim kinases in hematological malignancies: where are we now and where are we going?

The proviral insertion in murine (PIM) lymphoma proteins are a serine/threonine kinase family composed of three isoformes: Pim-1, Pim-2 and Pim-3. They play a critical role in the control of cell proliferation, survival, homing and migration. Recently, overexpression of Pim kinases has been reported in human tumors, mainly in hematologic malignancies. In vitro and in vivo studies have confirmed their oncogenic potential. Indeed, PIM kinases have shown to be involved in tumorgenesis, to enhance tumor growth and to induce chemo-resistance, which is why they have become an attractive therapeutic target for cancer therapy. Novel molecules inhibiting Pim kinases have been evaluated in preclinical studies, demonstrating to be effective and with a favorable toxicity profile. Given the promising results, some of these compounds are currently under investigation in clinical trials. Herein, we provide an overview of the biological activity of PIM-kinases, their role in hematologic malignancies and future therapeutic opportunities.     

Teaching history-taking: where are we?

Knowledge in history-taking has increased rapidly over the last twenty years. Currently the principles to be taught include "conduct," "content," and "diagnostic reasoning." However, inattentiveness of medical schools, reluctance of busy faculty to be involved, and increasing enrollments have resulted in difficulties in teaching these skills. Studies have shown a beneficial short-term effect of teaching these materials on interview performance but it is unknown whether this effect is long-lasting. The methods for instruction include the bedside and videotape models utilizing the concept of the fifteen-minute interview technique, programmed instruction, patient instructors, and direct student feedback. Future research should focus on identifying strategies in diagnostic reasoning, developing graduated competency criteria for trainees at different levels of their education, refining methods to evaluate large numbers of students, measuring outcomes of effective training such as compliance, and comparing costs and effectiveness of various methods. In addition, there remains the need to establish an association of course directors.     

Leptin in farm animals: where are we and where can we go?

Fat affects meat quality, value and production efficiency as well as providing energy reserves for pregnancy and lactation in farm livestock. Leptin, the adipocyte product of the obese (ob) gene, was quickly seen as a predictor of body fat content in animals approaching slaughter and an aid to assessing reproductive readiness in females. Its participation in inflammation and immune responses that help animals survive infection and trauma has clear additional relevance to meat and milk production. Furthermore, almost a decade of discoveries of nucleotide polymorphisms in the leptin and leptin receptor genes has suggested useful applications relating to feed intake regulation, the efficiency of feed use, the composition of growth, the timing of puberty, mammogenesis and mammary gland function and fertility in cattle, pigs and poultry. The current review attempts to summarise where research has taken us in each of these aspects and speculates on where future research might lead.     

Laser hair removal: where are we now?

The hair removal market is evolving rapidly. The goal has always been long-term epilation. Success is dependent on understanding hair biology and physiology and on knowledge of laser physics, skin optics, and tissue preservation with respect to these emerging laser technologies. These topics will be reviewed, as will specific categories of laser systems in the hair removal arena and the clinical aspects of laser hair removal today.     

Indonesia ergonomics roadmap: where we are going?

There are so many definitions for ergonomics terms such as human factors, human factors engineering, human engineering, human factors psychology, engineering psychology, applied ergonomics, occupational ergonomics, industrial ergonomics and industrial engineering. The most inclusive terms are ergonomics and human factors. Both represent the study of work and the interaction between people and their work environmental systems. The main objective is especially fitting with the need to design, develop, implement and evaluate human-machine and environment systems that are productive, comfortable, safe and satisfying to use. The work of the ergonomists in Indonesia--most of them are academicians--have one thing in common, i.e. with the appropriate type of ergonomic approaches to interventions; there would be improvements in productivity, quality of working conditions, occupational safety and health (OSH), costs reduction, better environment, and increase in profits. So many researches, training, seminars and socialization about ergonomics and OSH have been done concerning micro-to-macro themes; but it seems that we are practically still running at the same place up to now. In facts, workers are still working using their traditional or obsolete methods in poor working conditions. Accidents are still happening inside and outside industry with the main root-cause being human "unsafe behavior" and errors. Industrial products cannot compete in the global market, and so many manufacturing industries collapsed or relocated to foreign countries. This paper discusses such a roadmap and review what we ergonomists in Indonesia have done and where we are going to? This review will be treated in the field of ergonomics and OSH to take care the future Indonesia challenges. Some of the challenges faced are care for the workers, care for the people, care for the quality and productivity of work, care for the new advanced technologies, care for the environment, and last but not least care for the nation.     

Moderate ischemic mitral regurgitation (IMR) and metabolic syndrome: where are we now and where are we going?

Background

The metabolic syndrome appears to affect 10% to 25% of adult population worldwide. Several studies have described the association between metabolic syndrome and ischaemic heart disease, however, none linked metabolic syndrome to ischemic mitral regurgitation, a serious clinical problem facing both the cardiologists and cardiac surgeons. Ischemic mitral regurgitation is mitral insufficiency caused by myocardial infarction. The myocardial ischemia can result in altered ventricular geometry, leading to mitral insufficiency. Interestingly metabolic syndrome showed more pronounced alteration of left ventricular geometry and function especially in obese subjects.

Presentation of the hypothesis

We have recently proposed that there is link between metabolic syndrome and ischemic mitral regurgitation and associated complications. Operative strategy for moderate ischaemic mitral regurgitation continues to be debated between revascularisation alone and concomitant valve repair at the time of coronary artery bypass surgery. Each of the above group has published studies, with results supporting each argument.

Testing the hypothesis

Generally speaking the treatments available for metabolic syndrome are based in both life style modification (dietary advice and advice to increase physical activity) and medical treatment to enhance insulin sensitivity. Randomised controlled trials may show whether the current available treatment of metabolic syndrome may have an impact on moderate ischemic mitral regurgitation.

Implications of the hypothesis

Metabolic syndrome was shown to alter left ventricular geometry and therefore it is possible to postulate that the variation in the response of different patients with moderate ischemic mitral regurgitation to current management may be attributed to the absence and presence of metabolic syndrome. Research testing of this hypothesis in the future may reveal whether concomitant treatment of metabolic syndrome will play part in the management of moderate ischemic mitral regurgitation.     

Uncovering directional sensing: where are we headed?

We survey aspects of directional sensing, i.e. how a cell interprets differences in the external concentration of a chemoattractant to guide its motion, from the perspective of systems biology. We focus on questions that need to be addressed using a combination of modelling and experimental approaches. After briefly summarising the ideas underlying recent modelling efforts, we discuss a variety of experimental questions which are motivated by these models. Some of these questions focus on basic features of the chemotactic response, without involving much biochemistry, while others focus on filling some of the gaps in the biochemistry, which have been brought to light by the models. The emphasis is on systematic quantitative experiments that will unambiguously resolve many of these issues. Finally, we describe some current challenges for theoretical modelling and survey some of the theoretical tools and approaches employed to model the chemotaxis pathways.     

Utilizing proteomics to understand and define hypertension: where are we and where do we go?

Introduction: Hypertension is a complex and multifactorial cardiovascular disorder. With different mechanisms contributing to a different extent to an individual’s blood pressure, the discovery of novel pathogenetic principles of hypertension is challenging. However, there is an urgent and unmet clinical need to improve prevention, detection, and therapy of hypertension in order to reduce the global burden associated with hypertension-related cardiovascular diseases.

Areas covered: Proteomic techniques have been applied in reductionist experimental models including angiotensin II infusion models in rodents and the spontaneously hypertensive rat in order to unravel mechanisms involved in blood pressure control and end organ damage. In humans proteomic studies mainly focus on prediction and detection of organ damage, particularly of heart failure and renal disease. While there are only few proteomic studies specifically addressing human primary hypertension, there are more data available in hypertensive disorders in pregnancy, such as preeclampsia. We will review these studies and discuss implications of proteomics on precision medicine approaches.

Expert commentary: Despite the potential of proteomic studies in hypertension there has been moderate progress in this area of research. Standardized large-scale studies are required in order to make best use of the potential that proteomics offers in hypertension and other cardiovascular diseases.     

Oxidative stress and neurodegeneration: where are we now?

The brain and nervous system are prone to oxidative stress, and are inadequately equipped with antioxidant defense systems to prevent 'ongoing' oxidative damage, let alone the extra oxidative damage imposed by the neurodegenerative diseases. Indeed, increased oxidative damage, mitochondrial dysfunction, accumulation of oxidized aggregated proteins, inflammation, and defects in protein clearance constitute complex intertwined pathologies that conspire to kill neurons. After a long lag period, therapeutic and other interventions based on a knowledge of redox biology are on the horizon for at least some of the neurodegenerative diseases.     

Prostate cancer gene therapy-what have we learned and where are we going?

With recent advances in genetic engineering, tumor biology, and immunology, gene therapy has been recognized as a promising new treatment option for various cancers, including prostate cancer. Several clinical trials of prostate cancer gene therapy, using therapeutic genes which include suicide genes, immunomodulatory genes, tumor suppressor genes, and anti-oncogenes, are under way and preliminary reports have emerged. Although gene therapy for prostate cancer is still at an early stage and requires additional technological breakthroughs, new insights obtained from recent clinical trials indicate a promising potential for prostate cancer gene therapy. In this report, general concepts, current progress, and future prospects in prostate cancer gene therapy are summarized.     

Quantitative genetics,version 3.0: where have we gone since 1987 and where are we headed?

The last 20 years since the previous World Congress have seen tremendous advancements in quantitative genetics, in large part due to the advancements in genomics, computation, and statistics. One central theme of this last 20 years has been the exploitation of the vast harvest of molecular markers—examples include QTL and association mapping, marker-assisted selection and introgression, scans for loci under selection, and methods to infer degree of coancestry, population membership, and past demographic history. One consequence of this harvest is that phenotyping, rather than genotyping, is now the bottleneck in molecular quantitative genetics studies. Equally important have been advances in statistics, many developed to effectively use this treasure trove of markers. Computational improvements in statistics, and in particular Markov Chain Monte Carlo (MCMC) methods, have facilitated many of these methods, as have significantly improved computational abilities for mixed models. Indeed, one could argue that mixed models have had at least as great an impact in quantitative genetics as have molecular markers. A final important theme over the past 20 years has been the fusion of population and quantitative genetics, in particular the importance of coalescence theory with its applications for association mapping, scans for loci under selection, and estimation of the demography history of a population. What are the future directions of the field? While obviously important surprises await us, the general trend seems to be moving into higher and higher dimensional traits and, in general, dimensional considerations. We have methods to deal with infinite-dimensional traits indexed by a single variable (such as a trait varying over time), but the future will require us to treat much more complex objects, such as infinite-dimensional traits indexed over several variables and with graphs and dynamical networks. A second important direction is the interfacing of quantitative genetics with physiological and developmental models as a step towards both the gene–phenotype map as well as predicting the effects of environmental changes. The high-dimensional objects we will need to consider almost certainly have most of their variation residing on a lower (likely much lower) dimensional subspace, and how to treat these constraints will be an important area of future research. Conversely, the univariate traits we currently deal with are themselves projections of more complex structures onto a lower dimensional space, and simply treating these as univariate traits can result in serious errors in understanding their selection and biology. As a field, our future is quite bright. We have new tools and techniques, and (most importantly) new talent with an exciting international group of vibrant young investigators who have received their degrees since the last Congress. One cloud for concern, however, has been the replacement at many universities of plant and animal breeders with plant and animal molecular biologists. Molecular tools are now an integral part of breeding, but breeding is not an integral part of molecular biology.     

B-cell depletion for rheumatic diseases: where are we?

Immune system dysfunction is common to rheumatic disorders, with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) being classic examples. Altered development and function of B cells may play a prominent role. B-cell abnormalities also occur in other rheumatic diseases, eg, Sjogren's syndrome, Behcet's disease, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, and dermatomyositis. Hence, B-cell depletion has been investigated as a therapeutic option. Clinical trials in RA and SLE have shown that rituximab, an anti-CD20 monoclonal antibody, can profoundly reduce disease activity and is generally well tolerated. Reports of rituximab treatment for ANCA-associated vasculitis and dermatomyositis are also promising. These encouraging results validate the strategy of B-cell depletion in various rheumatic diseases. B-cell depletion with rituximab is under study in larger clinical trials for the purposes of regulatory approval to define more closely its place in RA and SLE treatment paradigms, and smaller clinical trials are ongoing or planned in associated inflammatory diseases.